The present invention provides novel heterocyclic compounds which have the calcium antagonistic and vasodilating properties, rendering these compounds useful in the treatment of cardiovascular disorders.
In the past fifteen years a series of 4-aryl-1,4-dihydropyridines has been synthesized and several of them have been investigated as calcium antagonists which are useful in treating myocardial ischemia, infarction or hypertention. Among them the following nifedipine (R.dbd.CH.sub.3, 2--NO.sub.2) and nicardipine ##STR3## 3--NO.sub.2) of the formula, ##STR4## are currently available for clinical uses.
There has been reported a few prior art related to the 1,4-dihydropyridines having a heterocyclic group at the 3- or 5-position of the pyridine ring. Poindexter, et al., U.S. Pat. No. 4,414,213 patented Nov. 8, 1983 disclose the dihydropyridines substituted at 5-position by 4,5-dihydro-2-oxazolyl. Schonafinger, et al., Eur. Pat. Appl. No. 116,708 laid open Aug. 29, 1984 disclose the dihydropyridines which relate to the instant invention, wherein the heterocyclic ring at 5-position is oxadiazolyl, thiadiazolyl or thiazolyl optionally bearing C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkylthio, C.sub.7 -C.sub.8 aralkyl, C.sub.2 -C.sub.5 alkoxyalkyl, C.sub.3 or C.sub.6 cycloalkyl, aminocarbonylmethylthio, methoxycarbonyl, ethoxycarbonyl or phenyl. The European Patent noted above also describes that the most preferable heterocyclic substituents include 1,3,4-oxadiazol-2-yl, 5-methyl-1,3,4-oxadiazol-2-yl, 5-ethyl-1,3,4-oxadiazol-2-yl, 3-methyl-1,2,4-oxadiazol-5-yl, 3-ethyl-1,2,4-oxadiazol-5-yl and 3-benzyl-1,2,4-oxadiazol-5-yl. Meyer reported in Calcium Antagonists and Cardiovascular Diseases, edited by Opie, L. H., Chapter 15 (1984) structure-activity relationships in the calcium antagonistic 1,4-dihydropyridines, where it is particularly concluded that carboxylic acid ester functions are optimal substituents at 3- and 5-position of the pyridine ring.